Browsing by Subject "MARKEDLY INCREASES"

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  • Itkonen, Matti K.; Tornio, Aleksi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabo-lites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC(0-infinity)) and peak plasma concentration (C-max) of desloratadine to 280% (P = 3 x 10(-7)) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 x 10(-7)) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC(0-71h) to 52% (P = 5 x 10(-5)) and 6%(P = 2 X 10(-8)), respectively. Moreover, the 3-hydroxydesloratadine: desloratadine AUC(0-71h) ratios were 21% (P = 7 x 10(-10)) and 1.7% (P = 8 x 10(-11)) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.
  • Itkonen, Matti K.; Tornio, Aleksi; Filppula, Anne M.; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2018)
    The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
  • Itkonen, Matti K.; Tornio, Aleksi; Lapatto-Reiniluoto, Outi; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2019)
    Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC(0-infinity) of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8 center dot 10(-7)), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC(0-infinity) 3.9-fold; range 2.1-7.9-fold (P = 2 center dot 10(-6)), compared with ritonavir alone. Ritonavir decreased the AUC(0-4h) of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.